The synaptic scaffolding protein CNKSR2 interacts with CYTH2 to mediate hippocampal granule cell development

Ito, Hidenori; Morishita, Rika; Noda, Mariko; Ishiguro, Tomoki; Nishikawa, Masashi; Nagata, Koh‐ichi

doi:10.1016/j.jbc.2021.101427

Cited by 5 publications

(1 citation statement)

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“…Recently, we clarified the participation of CNKSR2 in the development of the hippocampus [ 25 ]. We discovered that co-expression of CNKSR2 with CYTH2 or ARHGAP39 but not ARHGEF7 increased expression of CNKSR2.…”

Section: Interaction Of Cnksr2 With Cellular Signaling Moleculesmentioning

confidence: 99%

Functions of CNKSR2 and Its Association with Neurodevelopmental Disorders

Ito

Nagata

2022

Cells

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The Connector Enhancer of Kinase Suppressor of Ras-2 (CNKSR2), also known as CNK2 or MAGUIN, is a scaffolding molecule that contains functional protein binding domains: Sterile Alpha Motif (SAM) domain, Conserved Region in CNK (CRIC) domain, PSD-95/Dlg-A/ZO-1 (PDZ) domain, Pleckstrin Homology (PH) domain, and C-terminal PDZ binding motif. CNKSR2 interacts with different molecules, including RAF1, ARHGAP39, and CYTH2, and regulates the Mitogen-Activated Protein Kinase (MAPK) cascade and small GTPase signaling. CNKSR2 has been reported to control the development of dendrite and dendritic spines in primary neurons. CNKSR2 is encoded by the CNKSR2 gene located in the X chromosome. CNKSR2 is now considered as a causative gene of the Houge type of X-linked syndromic mental retardation (MRXHG), an X-linked Intellectual Disability (XLID) that exhibits delayed development, intellectual disability, early-onset seizures, language delay, attention deficit, and hyperactivity. In this review, we summarized molecular features, neuronal function, and neurodevelopmental disorder-related variations of CNKSR2.

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Section: Interaction Of Cnksr2 With Cellular Signaling Moleculesmentioning

confidence: 99%

Functions of CNKSR2 and Its Association with Neurodevelopmental Disorders

Ito

Nagata

2022

Cells

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Understanding neurodevelopmental proteasomopathies as new rare disease entities: A review of current concepts, molecular biomarkers, and perspectives

Cuinat,

Bézieau,

Deb

et al. 2024

Genes & Diseases

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Variations associated with neurodevelopmental disorders affect ARF1 function and cortical development

Ishiguro,

Noda,

Nishikawa

et al. 2024

The Journal of Biochemistry

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ADP-ribosylation factors (ARFs) are a family of small GTPases that regulate vesicle trafficking and actin dynamics in cells. Recent genetic analyses have revealed associations between variations in ARF genes and neurodevelopmental disorders, although their pathophysiological significance remains unclear. In this study, we conducted biochemical, cell biological, and in vivo analyses of ARF1 variants linked to neurodevelopmental disorders. The mant-GDP dissociation assay revealed that ARF1-p.R19C, -p.F51L, -p.R99C, and -p.R99H exhibit higher GDP/GTP exchange activity compared to ARF1 wild type (WT). The GTPase-activating protein (GAP) increased the GTPase activity of WT, p.R19C, p.Y35H, p.F51L, p.P131L, and p.P131R, but not of p.Y35D, p.T48I, p.R99C, and p.R99H. The transient expression of p.R99C, p.R99H, and p.K127E in mammalian cells resulted in the disruption of the Golgi apparatus. In utero electroporation-mediated gene transfer into the cortical neurons of embryonic mice demonstrated that p.R99C, p.R99H, and p.K127E cause a migration defect. Expression of these variants resulted in the expansion of the Golgi apparatus in migrating cortical neurons. These findings suggest that the ARF1 variants linked to neurodevelopmental disorders, specifically p.R99C, p.R99H, and p.K127E, disrupt the structure of the Golgi apparatus, thereby leading to a developmental defect of cortical neurons.

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The synaptic scaffolding protein CNKSR2 interacts with CYTH2 to mediate hippocampal granule cell development

Cited by 5 publications

References 50 publications

Functions of CNKSR2 and Its Association with Neurodevelopmental Disorders

Functions of CNKSR2 and Its Association with Neurodevelopmental Disorders

Understanding neurodevelopmental proteasomopathies as new rare disease entities: A review of current concepts, molecular biomarkers, and perspectives

Variations associated with neurodevelopmental disorders affect ARF1 function and cortical development

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